This project addresses fundamental neuroantomical issues about parts of the telencephalon, diencephalon and brainstem that are strongly influenced by mesotelencephalic dopamine and subserve spontaneous, purposeful behaviors. The structures involved comprise systems that are adversely affected in disease and drug abuse with resultant physical impairment and abnormal behavioral manifestations of enormous cost to American society. It is proposed to continue to develop a model of cortico- subcortical relationships dependent upon parallel, interconnected "functional-anatomical systems"- differentiated neural networks linking high-order association cortical areas and association cortex-like structures, such as the basal amygdala, with specific telencephalic structures, such as the central division of the extended amygdala and districts in the ventral parts of the basal ganglia associated with the nucleus accumbens core and shell. The patterns of intrinsic and extrinsic connections through which these systems interact with each other and structures in the diencephalon and brainstem will be addressed, as will their relationships with cell groups giving rise to ascending monoaminergic and cholinergic projections reported to control attention, vigilance, reward and locomotor activation. The objectives of the research are: to determine if [1a]cortical afferents of extended amygdala and shell of the accumbens arise from distinct subpopulations of neurons, [1b] outputs from different parts of the extended amygdala give rise to distinct patterns of termination, [2a] projections exist from the nucleus accumbens and extended amygdala to the cholinergic pedunculopontine tegmental nucleus and magnocellular basal forebrain neurons, and [2b] cholinergic neurons in the caudal part of the central extended amygdala are corticopetal. It is proposed also to characterize [3] the pattern of neuronal loss in the ventral tegmentum following neurotoxic lesions, [4] the chemospecificity and connections of basal forebrain neurotensin neurons that project to the ventral tegmental area and substantia nigrapars compacta, and [ 5] the connectional relationships of an until now unaddressed sector of the basal forebrain. The studies will be carried out with contemporary experimental neuroanatomical methods evaluated with the aid of qualitative and quantitative light, epifluorescence and electron microscopy. The experiments represent logical extensions of studies completed in preceding cycles of this grant. Each one addresses a specific question about neural relationships that will either (a) test the "functional-anatomical systems" model as currently configured or (b) extend the scope of the model. Knowledge about the organization and inter-relationships of forebrain functional- anatomical systems acquired through these studies will guide future studies addressing how multiple neural systems cooperate and compete in the synthesis of behavior and how the underlying processes are corrupted individually and collectively by neurodegenerative disease and substance abuse.